Role of Murr1 in HIV-1 latency

Carmen Martin Ruiz-Jarabo, J. David Gladstone Institutes
Biomedical and Clinical Sciences

Our immune system saves us from certain death by infection. In the absence of a working immune system, people may succumb to infections that often never occur in normal individuals. Such is the case with acquired immunodeficiency syndrome (AIDS) patients. AIDS is caused by the human immunodeficiency virus (HIV) which infects and kills a key component of the immune system, CD4 T cells. When HIV infects a CD4 T cell, it uses the host cell machinery to produce new virus which spread to other CD4 T cells while the original cell dies. To slow down HIV's inexorable assault on the immune system, a variety of drugs has been designed that interrupt different steps in the viral life cycle. Unfortunately, despite suppression of viral replication to undetectable levels through the use of combined antiretroviral therapy (ART), interruption of treatment invariably leads to a rapid rebound of virus. This rebound importantly involves virus residing in latently infected and long lived resting CD4 T cells. Latency occurs when HIV infects a cell and the viral DNA is integrated into the host DNA. But due to a loss of cellular activation, the integrated provirus may not be expressed. Since the virus in these latently infected cells is "silent" it is not vulnerable to ART, and healthy CD4 and CD8 T cells are unable to recognize these cells as HIV-infected lymphocytes. HIV eradication in infected patients will require a successful strategy for dealing with this latently infected reservoir of cells. One attractive strategy to eliminate this latent reservoir is to stimulate the expression of the silent viral genomes thereby enabling ART to act in latently infected cells. The NF-kappaB/Rel family of transcription factors represent key host factors that mediate the activation of latent HIV proviruses. We propose that these proteins have an important role in activating the latent virus. Preliminary data from our group and others suggest that, indeed, NF-kappaB related repressors are important in the maintenance of latency while transcriptionally active forms of NF-kappaB are important in the loss of latency. Recently, Murr1, a gene previously implicated in copper homeostasis, has been shown to function as a negative regulator of NF-kappaB activation. Murr1 inhibits both basal and stimulus-coupled induction of NF-kappaB by interfering with either the ubiquitylation or subsequent proteasome mediated degradaton of the NF-kappaB inhibitor, IkappaBalpha. We now propose to assess whether Murr1 plays a key role in the establishment and maintenance of HIV latency. If this proves to be the case, it could open the door to new strategies for limiting HIV latency through inhibition of the in vivo action of Murr1.